The human liver microenvironment shapes the homing and function of CD4 + T-cell populations.

Autor: Wiggins BG; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Pallett LJ; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Li X; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Department of Infectious Diseases and Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China., Davies SP; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Amin OE; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Gill US; Immunobiology, Blizard Institute, London, UK., Kucykowicz S; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Patel AM; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Aliazis K; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Liu YS; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Reynolds GM; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK., Davidson BR; Surgery, Royal Free Campus, UCL Medical School, London, UK., Gander A; Tissue Access for Patient Benefit, University College London, London, UK., Luong TV; Department of Cellular Pathology, Royal Free Hospital, London, UK., Hirschfield GM; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK.; Centre for Liver Research, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, UK., Kennedy PTF; Immunobiology, Blizard Institute, London, UK., Huang Y; Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Maini MK; Division of Infection and Immunity, Rayne Institute, University College London, London, UK z.stamataki@bham.ac.uk m.maini@ucl.ac.uk., Stamataki Z; Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK z.stamataki@bham.ac.uk m.maini@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Gut [Gut] 2022 Jul; Vol. 71 (7), pp. 1399-1411. Date of Electronic Publication: 2021 Sep 21.
DOI: 10.1136/gutjnl-2020-323771
Abstrakt: Objective: Tissue-resident memory T cells (T RM ) are vital immune sentinels that provide protective immunity. While hepatic CD8 + T RM have been well described, little is known about the location, phenotype and function of CD4 + T RM .
Design: We used multiparametric flow cytometry, histological assessment and novel human tissue coculture systems to interrogate the ex vivo phenotype, function and generation of the intrahepatic CD4 + T-cell compartment. We also used leukocytes isolated from human leukocyte antigen (HLA)-disparate liver allografts to assess long-term retention.
Results: Hepatic CD4 + T cells were delineated into three distinct populations based on CD69 expression: CD69 - , CD69 INT and CD69 HI . CD69 HI CD4 + cells were identified as tissue-resident CD4 + T cells on the basis of their exclusion from the circulation, phenotypical profile (CXCR6 + CD49a + S1PR1 - PD-1 + ) and long-term persistence within the pool of donor-derived leukcoocytes in HLA-disparate liver allografts. CD69 HI CD4 + T cells produced robust type 1 polyfunctional cytokine responses on stimulation. Conversely, CD69 INT CD4 + T cells represented a more heterogenous population containing cells with a more activated phenotype, a distinct chemokine receptor profile (CX 3 CR1 + CXCR3 + CXCR1 + ) and a bias towards interleukin-4 production. While CD69 INT CD4 + T cells could be found in the circulation and lymph nodes, these cells also formed part of the long-term resident pool, persisting in HLA-mismatched allografts. Notably, frequencies of CD69 INT CD4 + T cells correlated with necroinflammatory scores in chronic hepatitis B infection. Finally, we demonstrated that interaction with hepatic epithelia was sufficient to generate CD69 INT CD4 + T cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69 HI CD4 + T cells.
Conclusions: High and intermediate CD69 expressions mark human hepatic CD4 + T RM and a novel functionally distinct recirculating population, respectively, both shaped by the liver microenvironment to achieve diverse immunosurveillance.
Competing Interests: Competing interests: BW collaborated with and received funding from Bioniz. LJP sat on advisory boards/provided consultancy for Gilead Sciences and SQZ Biotech. KA was funded by a studentship with Dr Falk. MKM received research funding from Gilead Sciences, Hoffmann La Roche and Immunocore. MKM sat on advisory boards/provided consultancy for Gilead, Hoffmann La Roche, Immunocore, VIR, Galapagos NV, GSK, Abbvie and Freeline. ZS collaborated with Bioniz and AstraZeneca and consulted for Boehringer Ingelheim. All other authors declare no conflict of interest.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze: MEDLINE
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